T helper cells are critical for the proper function of the immune response and are essential for helping B cells make antibody. Follicular helper T (TFH) cells are a specialized subset of CD4+ T helper cells whose role is to help B cells produce high affinity antigen-specific antibody, and to promote the germinal center reaction. In the absence of TFH cells, germinal centers and secondary antibody responses cannot develop. However, excessive development of TFH cells is correlated with autoimmune disease. TFH cells are localized to germinal centers within B cell follicles due to their expression of the chemokine receptor CXCR5, and are further characterized by high expression of the transcription repressor BCL6 and the B cell stimulatory cytokine IL-21. Recent studies have shown that BCL6 is the master transcriptional regulator for TFH cells: forced BCL6 expression induces a TFH phenotype in T cells, and TFH cells cannot develop in the absence of BCL6. However, the mechanism for how BCL6 promotes the TFH phenotype is incompletely understood. Using a new BCL6 conditional knockout (cKO) mouse model, we have recently identified novel gene targets of BCL6 in CD4 T cells that are likely to play a role in TFH cell differentiation. In this proposal, we will seek to better define the role of a specific BCL6 target gene, IL-3. Our general hypothesis is that the novel BCL6 target gene IL-3 inhibits TFH function and that blocking IL-3 will increase the antibody response. This hypothesis will be tested in the proposal that follows. INNOVATION: We have identified a previously unknown regulatory pathway for how BCL6 controls TFH cell differentiation and will test this pathway functionally. We will investigate a novel strategy for increasing the efficacy of vaccination for the production of Ab. IMPACT: This study will provide insights into the unique developmental process of TFH cells, and will lead to the delineation of a new regulatory pathway that can be targeted to promote or inhibit TFH function. These experiments will provide information that is critical for understanding the development of the antibody response to fight infectious disease. These studies should aid in the development of vaccines that target TFH cells, and will also impact studies on autoantibody production.